Sulfate conjugation is an important pathway in the metabolism of many drugs, other xenobiotic compounds, hormones, and neurotransmitters. During the past two decades, the applicant's laboratory has systematically explored the pharmacogenetics of enzymes that catalyze sulfation in humans. As a result of application of the techniques of molecular biology, at least nine separate sulfotransferase (SULT) enzymes have now been identified in humans, including three phenol SULTs (1A1, 1A2, AND 1A3) that play an important role in the biotransformation of a large number of drugs. The applicant's laboratory demonstrated previously, at the biochemical level, that expression of phenol SULT activities in humans are controlled by genetic polymorphisms. In pursuit of those observations, the laboratory has recently cloned the genes for all three phenol SULTs in humans- a requirement for studies of molecular mechanisms responsible for the pharmacogenetic regulation of phenol sulfation in humans. It is now proposed to comprehensively define molecular genetic mechanisms involved in the regulation of the expression and function of phenol SULTs in humans by identifying polymorphisms within phenol SULT exons, 5'-flanking sequences and introns and determining which of these polymorphisms might be functionally significant. We will also expand our studies of sulfation pharmacogenetics in humans to include PAPS synthetase, the enzyme that catalyzes the synthesis of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), the sulfate donor for all mammalian SULT enzymes. We have already cloned the cDNA for this enzyme. We now propose to clone its gene and to determine possible molecular genetic mechanisms involved in differences among individuals in its expression and/or biochemical properties. The results of these experiments will increase our understanding of molecular mechanisms responsible for the genetic regulation of enzymes that catalyze the sulfate conjugation of drugs, other xenobiotic compounds, hormones and neurotransmitters in humans and may make it possible to predict individual variations in the sulfation and therefore, the effect or toxicity of these compounds.
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